In order to promote comprehensive quality assurance monitoring in the pharmaceutical industry the Food and Drug Administration (FDA) has initiated a program entitled the Process Analytical Technology (PAT) which is often defined as “a system for designing, analyzing, and controlling manufacturing through timely measurements (i.e. during processing) of critical quality and performance attributes of raw and in-process materials, and processes with the goal of ensuring final pharmaceutical product quality.” It is important to note that the term analytical in PAT is viewed broadly to include chemical, physical, microbiological, mathematical, and risk analysis conducted in an integrated manner. The approaches detailed in this disclosure are targeted for such monitoring and evaluation tasks.
Physical properties and mechanical integrity of drug tablets often affect their therapeutic functions. This disclosure presents non-contact/non-destructive techniques for determining the mechanical properties of coated tablets, such as Young's moduli, Poisson's ratios and mass densities as well as the thickness of the coating layer using an air-coupled approach is presented. Due to the elevated regulatory and competitive requirements, the demand for measuring and evaluating the mechanical properties of drug tablets has been increasing in the pharmaceuticals industry.
Compaction is a common production method for solid dosage formation from powder and/or granular materials in various industries. Solid dosage (e.g. drug tablets) cores are manufactured by applying pressure to a powder bed to compress the powder into a (porous) coherent/solid form. Compaction represents one of the most important unit operations in the pharmaceuticals industry. Physical and mechanical/elastic properties of the tablets, such as density, hardness and/or mechanical strength as well as geometric features, are determined during the compaction process. These properties can play crucial roles in pharmaceutical effectiveness and functions of a tablet such as tablet integrity and drug availability. The uniaxial compaction of a pharmaceutical powder results in an anisotropic and heterogeneous tablet with variations in such properties as density, porosity and mechanical strength throughout the tablet. During the compaction, various types of defect types can be created in tablets during compaction process, such as capping, chipping, cracking, and splitting. While many of these defect types can be easily identifiable through visual inspections of their exteriors, the defects formed in the interior of a tablet such as cracks are considerably more difficult to detect. Such invisible defects can result in functionally compromised tablets.
Some of the commonly defects occurred during compaction operation are as follows.
Capping is the term used, when the upper or lower segment of the tablet separates horizontally, either partially or completely from the main body of a tablet and comes off as a cap, during ejection from the tablet press, or during subsequent handling. Lamination is the separation of a tablet into two or more distinct horizontal layers. The main reason for these types of defect is that the air-entrapment in a compact during compression, and subsequent expansion of tablet on ejection of a tablet from a die causes capping and lamination.
Chipping is defined as the breaking of tablet edges, while the tablet leaves the press or during subsequent handling and coating operations. The major reasons of chipping include incorrect machine settings and specially mis-set ejection take-off.
Cracking (small, fine cracks) observed on the upper and lower central surface of tablets, or very rarely on the sidewall is often as a result of rapid expansion of tablets, especially when deep concave punches are used. Many mechanical and materials factors such as stress localization and poor adhesion conditions can cause cracks in a tablet core.
Cracking/Splitting is defect in which the film either cracks across the crown of the tablet (cracking) or splits around the edges of the tablet (Splitting) under internal stresses in the film that exceeds tensile strength of the film. Sticking refers to the tablet material adhering to the die wall. Filming is a slow form of sticking and is largely due to excess moisture in the granulation (due to improperly dried or improperly lubricated granules).
Picking is the term used when a small amount of material from a tablet is sticking to and being removed off from the tablet-surface by a punch face. Picking defect is more prevalent on the upper punch faces than on the lower ones. If tablets are repeatedly manufactured in this station of tooling, the size of the defect becomes larger the more and more material getting added to the already stuck material on the punch face. Picking is of particular concern when punch tips have engraving or embossing letters, as well as the granular material is improperly dried.
When the tablets adhere, seize or tear in the die, a film is formed in the die and ejection of tablet is hindered. This type of defect is termed as binding. With excessive binding, the tablet sides are cracked and it may crumble apart. Binding is usually due to excessive amount of moisture in granules, lack of lubrication and/or use of worn dies.
In recent years, deformation and compaction characteristics of the tableting materials have been intensely studied. See: Fell J. T., Newton, J. M., 1968, Tensile strength of lactose tablets, The Journal of Pharmacy and Pharmacology, 20, 657-659; Fell J. T., Newton, J. M., 1970, The prediction of the tensile strength of tablets, The Journal of Pharmacy and Pharmacology, 22, 247; Hancock, B. C., Colvin, J. T., Mullarney, M. P. Zinchuk, A. V., 2003, The relative densities of pharmaceutical powders, blends, dry granulations, and immediate-release tablets, Pharmaceutical Technology, 27, 64-80 (Payne et al.); R. S., Roberts R. J., Rowe R. C., McPartlin M., Bashall A., 1996, The mechanical properties of two forms of primidone predicted from their crystal structures, International Journal of Pharmaceutics, 145, 165-173 (Robert et al.); Roberts R. J., Payne R. S., Rowe R. C., 2000, Mechanical property predictions for polymorphs of sulphathiazole and carbamazepine, European Journal of Pharmaceutical Sciences, 9, 277-283; Roberts R. J., Rowe R. C., 1987, The Young's modulus of pharmaceutical materials, International Journal of Pharmaceutics, 37, 15-18; Bassam F., York P., Rowe R. C., Roberts R. J., 1990, Young's modulus of powders used as pharmaceutical excipients, International Journal of Pharmaceutics, 64, 55-60; and Rigdway K., Aulton M. E., 1970, The surface hardness of tablets, Journal of Pharmacy and Pharmacology, 22, 70-78, all hereby incorporated herein by reference.
One main objective has been to determine the powder behavior during compaction and to understand the effect of the processing of tableting stages on the compaction properties of final products. Even though physical-mechanical properties of tablets are known to influence the tablet chemical and physical stability, accuracy of dosage and appropriate self life, few studies have focused on properties such as the Young's modulus, tensile strength and Poisson's ratio of the core and coating layer of the tablets. See Felton L. A., Shah N. H., Zhang G., Infeld M. H., Malick A. W., McGinity J. W., 1996, Physical-mechanical properties of film-coated soft gelatin capsules, International Journal of Pharmaceutics, 127, 203-211 (Felton et al.); and Stanley P., Rowe R. C. and Newton J. M., 1981, Theoretical considerations of the influence of polymer film coatings on the mechanical strength of tablets. Journal of Pharmacy and Pharmacology, 33, 557-560 both hereby incorporated by reference.
Fell and Newton as cited above investigated the tensile strength of the tablets by diametrical compression tests. Felton et al. as cited above studied the physical-mechanical properties of film-coated tablets including tensile strength, Young's modulus and tensile roughness using a diametrical compression test. In a diametrical compression test as discussed by Fell and Newton, the tablet is placed between two jaws and crushed. The force applied to break the tablet is recorded along with the outer dimensions of the tablet and tensile strength is calculated. The determination of the tensile strength of individual tablet components is used to predict the resultant tensile strength of tablet as a whole.
An important objective of the physical-mechanical property of coating films is to predict the stability and release property of film-coated dosage forms. Tablet coating has been effectively used to protect the dosage form from its environment, to control the release of active ingredients in the body, and to prevent interactions between ingredients. Additionally, tablet coating has improved the mechanical strength of the dosage form to preserve tablet integrity during packaging and shipping. Several researchers have focused on tensile strength and the elastic modulus of free-standing films prepared via aqueous coating technology. See Gutierrez-Rocca J. C. and McGinity J. W., 1993, Influence of aging on the physical-mechanical properties of acrylic resin films cast from aqueous dispersions and organic solutions, Drug Development and Industrial Pharmacy, 19, 315-332; Gutierrez-Rocca J. C. and McGinity J. W., 1994, Influence of water soluble and insoluble plasticizers on the physical and mechanical properties of acrylic resin copolymers, International Journal of Pharmaceutics, 103, 293-301; and Obara S, and McGinity J. W., 1994; Properties of free films prepared from aqueous polymers by a spraying technique; Pharmaceutical Research, 11, 1562-1567, all hereby incorporated by reference. The Obara and McGinty study cited above compared the properties of cast films to sprayed films. It has been reported that the mechanical property variation of the sprayed films are lower and their tensile strength are higher than those of the cast films.
Payne et al. and Roberts et al. (both cited above) developed a molecular modeling approach for predicting Young's moduli of compacts and tableting materials. A mechanical model of crystal structure was used to determine the crystal lattice energy, from which Young's moduli of a series of compacts prepared from aspirin and polymorphs of primidone, carbamazepine and sulphathiazole could be extracted. However, reportedly it is difficult to obtain the bulk elastic properties of tablet materials from the first principles based on molecular dynamic simulations.
Acoustic emission (AE) techniques during processes have been widely utilized in the pharmaceuticals industry due to its cost effective and noninvasive nature for monitoring granular materials to predict their flow, particle size and compaction properties of the final granules. Wong et al. differentiate the deformation mechanisms of single crystals of lactose monohydrate and anhydrous lactose by acoustic emission. It is reported that acoustic emission techniques can be employed to predict the compaction properties and brittleness of tableting materials if the bulk material is characterized by a single-crystal. See: Wong D. Y. T., Waring M. J., Wright P. and Aulton M. E., 1991, Elucidation of the compressive deformation behavior of α-lactose monohydrate and anhydrous α-lactose single crystals by mechanical strength and acoustic emission analyses, International Journal of Pharmaceutics, 72, 233-241 (Wong et al.) hereby incorporated by reference.
Waring et al. and Hakanen and Laine investigated the acoustic emission of lactose, sodium chloride, microcrystalline cellulose and paracetamol during compression using an acoustic transducer coupled to a portable activity meter. See Hakanen A., Laine E., 1993, Acoustic emission during powder compaction and its frequency spectral analysis, Drug Development and Industrial Pharmacy, 19, 2539-2560 (Waring et al.); and Hakanen A., Laine E., 1995, Acoustic Characterization of a micro-crystalline cellulose powder during and after its compression, Drug Development and Industrial Pharmacy, 21, 1573-1582, hereby incorporated by reference. By computationally analyzing the acoustic peaks related with the particle compression and decompression, it is concluded that the deformation mechanism and capping tendency can be predicted (See Hakanen and Laine cited above). Measuring acoustic emission from process chambers is also used for the identification of various phenomena that can occur during powder compaction of pharmaceutical products, such as granular rearrangement, fragmentation, visco-plastic deformation of grains or granules. See Serris E., Camby-Perier L., Thomas G., Desfontaines M., Fantozzi G., 2002. Acoustic Emission of Pharmaceutical Powders during Compaction, Powder Technology, 128, 2-3, 296-299. Acoustic emission is a passive acoustic technique thereby control over the nature of excitation is often limited.
Hardy and Cook reviewed the use of near infrared spectroscopy (NIR), a non-destructive remote technique as being primarily used for monitoring and predicting the end-points of granulation and drying operations. See Hardy I. J. and Cook W. G., 2003, Predictive and correlative techniques for the design, optimization and manufacture of solid dosage forms, Journal of Pharmacy and Pharmacology, 55 (1), 3-18 hereby incorporated by reference. The potential use of NIR has also been studied to predict tablet hardness. See Morisseau K. M., Rhodes C. T., 1997, Near-infrared spectroscopy as a nondestructive alternative to conventional tablet hardness testing, Pharmaceutical Research, 14 (1), 108-111; Kirsch J. D., Drennen J. K., 1999, Nondestructive tablet hardness testing by near-infrared spectroscopy: a new and robust spectral best-fit algorithm. Journal of Pharmaceutical and Biomedical Analysis, 19 (3-4), 351-362; Chen Y. X., Thosar S. S., Forbes s R. A., Kemper M. S., Rubinovitz R. L., Shukla A. J., 2001, Prediction of drug content and hardness of intact tablets using artificial neural network and near-infrared spectroscopy, Drug Development and Industrial Pharmacy, 27 (7), 623-631;
Donoso M., Kildsig D. O., Ghaly E. S., 2003, Prediction of tablet hardness and porosity using near-infrared diffuse reflectance spectroscopy as a nondestructive method, Pharmaceutical Development and Technology, 8 (4), 357-366; Blanco M., Alcala M., 2006, Content uniformity and tablet hardness testing of intact pharmaceutical tablets by near infrared spectroscopy—A contribution to process analytical technologies, Analytica Chimica Acta, 557 (1-2): 353-359; and Otsuka M., Yamane I., 2006, Prediction of tablet hardness based on near infrared spectra of raw mixed powders by chemometrics, Journal of Pharmaceutical Sciences, 95, 1425-1433; all hereby incorporated by reference. However, its sensitive calibration and validation requirements for tablet hardness models remain a challenge since it is known that a slight variation in spectral peaks could invalidate a model.
Many solid pharmaceutical dosage mediums are produced with coatings, ideally the tablet should release the material gradually and the drug should be available for digestion beyond the stomach. Tablet coats serve a wide range of purposes, such as to control release of active ingredients in the body, to avoid irritation of oesophagus and stomach, and to protect the stomach from high concentrations of active ingredients, to improve drug effectiveness and stability and to regulate and/or extend dosing interval. In addition coats extend shelf life by protecting the ingredients from degradation, and to enhance the drug stability; that is to protect the drug from moisture, environmental gases, temperature variations and light, to provide a barrier to unpleasant taste or odor, and to improve appearance and acceptability as well as product identity (Cetinkaya et al., 2006; Mathiowitz, 1999). Coatings that form a controlling barrier to the release of the active ingredient and impart a sustained release of the drug are valuable delivery systems that provide convenience as well as patient compliance. Especially this is true for functional coatings such as an enteric coating which is designed to protect the tablet from the acidic environment of the stomach, resulting in drug release in the higher pH environment of the small intestine. Non-uniformity and/or surface or sub-surface defects of the tablet coating can compromise the desired dose delivery and bioavailability of the drug tablet as well as some other functions. Therefore, evaluating the properties of pharmaceutical coatings such as thickness and uniformity is important for demonstrating adequate process controls and quality and for ensuring optimal performance of the final product. As discussed above, in relation to quality and assurance, the Food and Drug Administration (FDA) has initiated a program entitled the Process Analytical Technology (PAT) to address various aspects of manufacturing problems in the pharmaceuticals industry. The PAT initiative is intended to improve consistency and predictability of drug action by improving quality and uniformity of pharmaceutical materials (Hussain et al., 2004).
In the pharmaceuticals industry, various techniques have been employed in coating thickness measurements such as ultrasonic measurements (Akseli et al., 2007), laser induced breakdown spectroscopy (LIBS) (Mowery et al., 2002), x-ray fluorescence method (Behncke, 1984), short pulsed of electromagnetic radiation (e.g. TeraHertz pulsed spectroscopy) (Fitzgerald et al., 2005), scanning thermal microscopy and Fourier transform infrared (FTIR) spectroscopy (Felton, 2003). In contact pulse-echo acoustic measurements, short ultrasonic pulses are generated by a piezoelectric transducer to transmit through the tablet. The ultrasonic pulse is reflected from the back side of the tablet and returned to the measurement surface via the shortest possible path. The reflected waveforms are captured by the same transducer and digitized in the oscilloscope. Measuring the displacement of the first back-wall echo from the start of the transmission peak, the longitudinal velocity of sound can be computed (Akseli et al., 2007). The thickness can then be calculated from the calibration of the time base. Throughout these measurements, coupling medium (water, grease, oil, and couplant gel) is required for facilitating the transmission of ultrasonic energy from the transducer into the test specimen.
Short pulsed of electromagnetic radiation and its reflections from interfaces (e.g. TeraHertz pulsed spectroscopy) is used for the analysis of coating thickness of tablets however due to its high cost it is difficult to use this technique in practice. Scanning thermal microscopy, laser induced breakdown spectroscopy (LIBS), x-ray fluorescence method and Fourier transform infrared (FTIR) spectroscopy are either expensive or unavailable for rapid online measurements for coating thicknesses of drug tablets. The proposed technique has potential to fulfill a major need in the analysis of drug delivery mechanisms.
Other relevant non-contact techniques for mechanical property determination adopted in various industrial applications include: (i) EMAT (Electro-Magnetic Acoustic Transducer)-based systems, (ii) optical methods, (iii) spectroscopy-based approaches (IR, near-IR, Raman scattering, Plasmon resonance). Nondestructive testing technologies based on EMATs are inapplicable to the determination of mechanical properties of tablets since tablet materials are typically not electrically conductive. Optical methods are often limited to surface, or near-surface properties, and are often irrelevant in sub-surface mechanical property analysis since, in general, drug tablets and coating layers are opaque in the visible and non-visible ranges. In tablet integrity applications, optical techniques are considered indirect methods for mechanical property monitoring and evaluation. For several years, spectroscopic techniques have been used in monitoring various process parameters such as moisture (water and/or alcohol levels) and blending properties of powders. In these measurements, surface properties are sufficient but the penetration of the electromagnetic waves inside the tablet is typically not required and/or not possible. There is no general method to predict the Young's modulus and Poisson's ratios of the core and coating layer of a tablet from the properties of its constituent components even if exact process steps are known. Non-contact acoustic techniques, detailed in this disclosure, have certain advantages in testing and evaluating the mechanical integrity of the core and the coating layer of drug tablets because of the ability for acoustic waves to penetrate the tablet surface and to vibrate entire tablet structures.
Background of Invention Section Disclaimer: To the extent that specific patents/publications/products are discussed above in this Background of Invention Section or elsewhere in this Application, these discussions should not be taken as an admission that the discussed patents/publications/products are prior art for patent law purposes. For example, some or all of the discussed patents/publications/products may not be sufficiently early in time, may not reflect subject matter developed early enough in time and/or may not be sufficiently enabling so as to amount to prior art for patent law purposes. To the extent that specific patents/publications/products are discussed above in this Background of Invention Section and/or throughout the application, the descriptions/disclosures of which are all hereby incorporated by reference into this document in their respective entirety(ies).